The death rate and hospitalizations from chronic obstructive pulmonary disease (COPD) have doubled in the last 50 years. A third of COPD hospitalizations overlap with heart failure, mostly with preserved ejection fraction (HFpEF), yet no large COPD study has ascertained cardiac function. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study was funded to test the endothelial hypothesis of emphysema and examine reduced RV dimensions (?cor pulmonale parvus?) in COPD. In the MESA COPD Study II, we found that associations of reduced pulmonary microvascular blood flow with emphysema do not appear to be confounded by hypoxic pulmonary vasoconstriction and that emphysema on CT predicted RV regression over 5 years. We also developed methods to further subtype emphysema and COPD and scaled them up to the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS). We used unsupervised machine learning to discover new emphysema subtypes that are common and have molecular origins. Separately, we found that 26% of adults have segmental airway variants, which are associated with COPD and the developmental genes FGF10 and RARA. Both genes affect right heart development. In pilot work, we found one dramatically altered RV strain and the other associated with cor pulmonale parvus. Finally, we found that bronchitic ?symptomatic smokers,? who have hyperinflation from gas trapping, may have increased LV diastolic dysfunction. Hence, cardiac alterations in COPD are complex but recent advances in COPD subtyping may allow their personalized diagnosis and treatment. SPIROMICS is an NHLBI-funded prospective study that recruited smokers with COPD and controls and is re-examining 2,000 participants with gold- standard lung phenotyping including full-lung CT. We propose to add comprehensive echocardiography (echo) with speckle-tracking for cardiac mechanics for 1,000 SPIROMICS participants, with exercise in 700 and cardiopulmonary MRI in 600, to test the following hypotheses: 1) machine-learned subtypes of emphysema on CT are associated with specific alterations in cardiac structure and function, which vary from cor pulmonale to LV diastolic dysfunction; 2) participants with segmental airway variants have abnormal RV structure and function; 3) symptomatic smokers have signs of increased LV afterload and LV diastolic dysfunction. Innovative aspects of the application include the use of novel echo and MRI measures in a large, well- characterized cohort of COPD patients. Confirmation of the hypotheses would define the mechanisms of HFpEF in COPD and identify subsets of patients for targeted treatment of cardiopulmonary dysfunction.